The upregulation of specific interleukin (IL) receptor antagonists and paradoxical enhancement of neuronal apoptosis due to electrode induced strain and brain micromotion
The upregulation of specific interleukin (IL) receptor antagonists and paradoxical enhancement of neuronal apoptosis due to electrode induced strain and brain micromotion
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DOI：
10.1016/j.biomaterials.2012.05.021
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发表时间：
2012-09-01
期刊：
影响因子：
14
通讯作者：
Bellamkonda, Ravi V.
中科院分区：
文献类型：
--
作者：
Karumbaiah, Lohitash;Norman, Sharon E.;Bellamkonda, Ravi V.
硅微电极和金属微电极的刚度与软皮质组织之间的高度机械失配在神经界面处诱导应变，这可能导致神经界面失效。然而，关于电极诱导的低量级应变（1 - 5%）对原代星形胶质细胞、小胶质细胞和神经元的分子结果知之甚少。在这项研究中，我们模拟脑微动电极脑界面的星形胶质细胞，小胶质细胞和初级皮质神经元低幅度的周期性应变使用双轴拉伸装置，并研究了在体外诱导应变的分子结果。此外，我们探讨了星形胶质细胞和小胶质细胞应变对神经健康的功能后果，当他们自己受到应变。拉伸的星形胶质细胞和小胶质细胞的定量实时PCR阵列（qRT-PCR阵列）分析显示白细胞介素受体拮抗剂- IL-36 Ra（先前为IL-1F 5）的菌株特异性上调，分别为类似于1018倍和类似于236倍。此外，IL-36 Ra基因表达在用细菌脂多糖（LPS）处理的星形胶质细胞和小胶质细胞中保持不变，表明在拉伸的星形胶质细胞和小胶质细胞中观察到的上调可能是菌株特异性的。酶谱和蛋白质印迹分析表明，机械紧张的星形胶质细胞和小胶质细胞上调基质金属蛋白酶（MMPs）2和9，以及其他反应性胶质细胞增生的标志物，如胶质细胞酸性蛋白（GFAP）和神经聚糖相比，控制。当用和不用IL-36 Ra拉伸时，原代皮质神经元显示肿瘤坏死因子受体超家族成员IIb（TNFRSF 11b）的类似400倍下调。与不存在IL-36 Ra相比，在IL-36 Ra存在下还观察到胱天蛋白酶半胱氨酸蛋白酶家族成员和其他促凋亡基因的显著上调。植入微丝电极的成年大鼠显示IL-36 Ra上调（相似于20倍）和IL-1 Ra（类似于1500倍），证实了体外结果，尽管这些转录物相对于3 DPI的表达水平大幅下调了类似于20倍和类似于1488倍，在植入后12周结束时（12 WPI）。这些结果表明，IL受体拮抗剂可能在电极植入后的急性时间点对神经元健康产生负面影响。(C)2012爱思唯尔有限公司保留所有权利。
The high mechanical mismatch between stiffness of silicon and metal microelectrodes and soft cortical tissue, induces strain at the neural interface which likely contributes to failure of the neural interface. However, little is known about the molecular outcomes of electrode induced low-magnitude strain (1 -5%) on primary astrocytes, microglia and neurons. In this study we simulated brain micromotion at the electrode brain interface by subjecting astrocytes, microglia and primary cortical neurons to low-magnitude cyclical strain using a biaxial stretch device, and investigated the molecular outcomes of induced strain in vitro. In addition, we explored the functional consequence of astrocytic and microglial strain on neural health, when they are themselves subjected to strain. Quantitative real-time PCR array (qRT-PCR Array) analysis of stretched astrocytes and microglia showed strain specific upregulation of an Interleukin receptor antagonist - IL-36Ra (previously IL-1F5), to similar to 1018 and similar to 236 fold respectively. Further, IL-36Ra gene expression remained unchanged in astrocytes and microglia treated with bacterial lipopolysaccharide (LPS) indicating that the observed upregulation in stretched astrocytes and microglia is potentially strain specific. Zymogram and western blot analysis revealed that mechanically strained astrocytes and microglia upregulated matrix metalloproteinases (MMPs) 2 and 9, and other markers of reactive gliosis such as glial fibrillary acidic protein (GFAP) and neurocan when compared to controls. Primary cortical neurons when stretched with and without IL-36Ra, showed a similar to 400 fold downregulation of tumor necrosis factor receptor superfamily, member lib (TNFRSF11b). Significant upregulation of members of the caspase cysteine proteinase family and other pro-apoptotic genes was also observed in the presence of IL-36Ra than in the absence of IL-36Ra. Adult rats when implanted with microwire electrodes showed upregulation of IL-36Ra (similar to 20 fold) and IL-1Ra (similar to 1500 fold) 3 days post-implantation (3 DPI), corroborating in vitro results, although these transcripts were drastically down regulated by similar to 20 fold and similar to 1488 fold relative to expression levels 3 DPI, at the end of 12 weeks post-implantation (12 WPI). These results demonstrate that IL receptor antagonists may be negatively contributing to neuronal health at acute time-points post-electrode implantation. (C) 2012 Elsevier Ltd. All rights reserved.